BL-M11D1, a Novel CD33 Antibody-Drug Conjugate (ADC), in Patients with Relapsed/ Refractory Acute Myeloid Leukemia: Initial Results from First-in-Human Phase 1 Study

Background: BL-M11D1 is a novel ADC consisting of a CD33 monoclonal antibody bound to a novel TOP-I inhibitor payload via a cleavable linker. Here, we report the initial results of a phase I clinical trial of BL-M11D1 in relapsed/refractory (R/R) AML patients. Methods: This study enrolled patients with R/R AML aged 18-75 years. For dose escalation (D-ESC i3+3), BL-M11D1 was administrated intravenously in dose cohorts from 0.6mg/kg up to 4.4mg/kg once a week (QW) in 28-day cycles for induction treatment, followed by administration every two weeks (Q2W) at the same initial dose for consolidation treatment in pts whose bone marrow (BM) blast ＜5%. A subset of pts were enrolled in dose-expansion (D-EXP) at 1.65, 2.2 mg/kg doses. Results: As of July 25, 2024, 39 patients were enrolled at doses ranging from 0.6 mg/kg to 2.75 mg/kg, with a median age of 53.9 years (range: 19-75 years), including 2 patients with secondary AML. Among them, 10 patients had primary refractory AML, 24 had refractory AML, and 5 had relapsed AML. The median number of prior treatment lines was 4 (range 1-9), including 2 patients who had a previous autologous stem cell transplant. No dose-limiting toxicities (DLTs) were observed at the time of the cutoff date. The most common treatment-related adverse events (TRAEs) in ≥20% of pts were white blood cell count decreased (56.4%), anemia (51.3%), hypokalemia (51.3%), platelet count decreased (51.3%), neutrophil count decreased (46.2%), hypoalbuminemia (43.6%), hyponatremia (35.9%), nausea (35.9%), ALT increase (33.3%), pyrexia (28.2%), lymphocyte count decreased (25.6%), vomiting (25.6%), abdominal distension (23.1%), diarrhea (23.1%), and hypoproteinemia (20.5%). Grade ≥3 non-hematologic TRAEs were hypokalemia (25.6%), pneumonia (15.4%), infection (12.8%), pyrexia (5.1%), nausea (5.1%), febrile infection (5.1%), bilirubin increased (5.1%), GGT increase (5.1%), ALP increase (5.1%), ALT increase (2.6%), diarrhea (2.6%), AST increase (2.6%). One patient discontinued treatment. There was no dose reduction necessitated by TRAEs. Two pts died due to infection, which might be associated with BL-M11D1 by investigators' evaluation. No grade 3 or higher organ injury has been seen to date, and no veno-occlusive disease (VOD) observed in any patient. Responses have been seen starting at the 1.65 mg/kg dose, with a complete response (CR) of 6+ months duration observed. At doses of 1.65 mg/kg, 2.2 mg/kg and 2.75 mg/kg, 7 pts, 14 pts and 4 pts respectively have been evaluable for efficacy (at least 1 post-treatment assessment). The overall response rate (ORR)* at these doses are 14.3% (1/7), 42.9% (6/14) and 50% (2/4), respectively. Note: *ORR including CR, CR with incomplete hematologic recovery (CRi), and morphologic leukemia free state (MLFS). Conclusion: The preliminary results of this phase I study have demonstrated BL-M11D1 monotherapy with an acceptable safety profile and encouraging anti-cancer activity, including in refractory patients who had not previously achieved remission from prior therapy. The dose escalation of BL-M11D1 is ongoing, to better define the safety profile, anti-cancer activity and the RP2D for future development.